Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection

CD4(+) T cells contribute critically to a protective immune response during intestinal infections, but have also been implicated in the aggravation of intestinal inflammatory pathology. Previous studies suggested that T helper type (Th)1 and Th17 cells depend on de novo fatty acid (FA) synthesis for their development and effector function. Here, we report that T-cell-specific targeting of the enzyme acetyl-CoA carboxylase 1 (ACC1), a major checkpoint controlling FA synthesis, impaired intestinal Th1 and Th17 responses by limiting CD4(+) T-cell expansion and infiltration into the lamina propria in murine models of colitis and infection-associated intestinal inflammation. Importantly, pharmacological inhibition of ACC1 by the natural compound soraphen A mirrored the anti-inflammatory effects of T-cell-specific targeting, but also enhanced susceptibility toward infection with C. rodentium. Further analysis revealed that deletion of ACC1 in ROR gamma t(+) innate lymphoid cells (ILC), but not dendritic cells or macrophages, decreased resistance to infection by interfering with IL-22 production and intestinal barrier function. Together, our study suggests pharmacological targeting of ACC1 as an effective approach for metabolic immune modulation of T-cell-driven intestinal inflammatory responses, but also reveals an important role of ACC1-mediated lipogenesis for the function of ROR gamma t(+) ILC.

Automated summary

This study demonstrates that targeting the enzyme ACC1 can impair intestinal Th1 and Th17 responses by limiting CD4(+) T-cell expansion and infiltration, suggesting ACC1 as a potential target for modulating T-cell-driven intestinal inflammatory responses. However, inhibition of ACC1 also increases susceptibility to infection with C. rodentium and highlights the importance of ACC1-mediated lipogenesis in ROR gamma t(+) ILC function.